This application is a 371 of PCT/EP98/03546 filed Jun. 12, 1998.
The invention relates to the use of monolithic sorbents, particularly ones containing separation effectors, for preparative chromatographic separation processes, and also to a process for the preparative chromatographic separation of at least two substances using monolithic sorbents.
The aim of preparative chromatographic separation processes is the isolation of the purified substance. In contrast thereto, analytical chromatographic separation processes are directed at a high selectivity at a low bandwidth. Analytic processes do not serve for the isolation of the substance and additional analytical procedures (e.g. mass spectrometry, UV/VIS spectrometry) follow the separation process. For preparative chromatographic separation processes, the optimum compromise between chromatographic resolution and productivity is important.
To achieve good economics for preparative material separations, it is important to achieve high flow rates and short elution times and to maintain moderate operating pressures. The separation performance of a chromatographic column is characterized by the theoretical plate height (or number of theoretical plates per metre). The relationships to flow and diffusion processes are described by the van Deemter equation. If the diameter of the sorbent particles is increased, the number of theoretical plates decreases and the column has to be made longer so as not to reduce the separation performance. If the diameter of the sorbent particles is increased, the number of theoretical plates becomes relatively strongly dependent on the flow rate. Thus, the achievable chromatographic separation performance is in many cases greatly dependent on the flow rate selected (steep H(u) curve). The relationships mentioned are basically known to a person skilled in the art and are described in manuals such as xe2x80x9cHandbuch der HPLCxe2x80x9d (K.K. Unger, ed.; GIT-Verlag, Darmstadt, DE). In contrast thereto, it has been found that in the use according to the invention of monolithic sorbents, the pore diameter of the macropores can be varied without the dimensions of the skeleton phase located between the macropores having to be varied. As a result, the pressure drop can be reduced by choice of a sorbent having larger macropores while the increased flow rate barely influences the separation performance.
In preparative material separations, countercurrent processes have become important. Since it is technically very difficult to achieve actual movement of a stationary phase, the movement of the stationary phase is simulated. For this purpose, the overall column bed is divided into individual columns which are cyclically connected in series. The total number of columns is typically a multiple of four, since such a system has four chromatographic zones. After a defined time, the lines are switched around, which simulates movement of the column bed in the opposite direction. Further details regarding the mode of operation of SMB chromatography may be found, for example, in WO 97/47 617. For continuous xe2x80x9csimulated moving bedxe2x80x9d chromatography (SMB chromatography), particulate sorbents are customarily used as separation materials. The column packings used do not allow optimum flow rates, since the operating pressure is very high for particulate supports. Furthermore, the mechanical stability of the particulate sorbent beds is not very good. In addition, SMB chromatography requires a series of chromatographic columns (typically up to 24) having virtually identical properties to be provided. In the case of particulate sorbent beds, this can be achieved only with great effort when packing the columns and with selection of the packed columns.
It is an object of the invention to provide chromatographic preparative separation processes, in particular for the SMB method, which have high flow rates at a moderate operating pressure.
It has been found that monolithic sorbents can be used for separation processes operating at high flow rates; thus, a higher throughput per unit time, i.e. improved productivity, can be achieved. The productivity achievable in separation processes according to the invention using monolithic sorbents is typically an order of magnitude higher than in separation processes using particulate sorbents.
The invention provides a process for the preparative chromatographic separation of at least two substances, especially by the SMB method, wherein the stationary phase used is a monolithic sorbent based on shaped SiO2 bodies whose macropores have diameters in the range from 2 to 20 xcexcm and whose mesopores have diameters in the range from 2 to 100 nm (in each case median values).